Pancuronium, Org 6368 and gallamine were compared in control cats and in cats with experimental cholestasis. A decrease in the plasma clearance and a prolongation of neuromuscular blockade with Org 6368 and pancuronium were found in the latter; no significant difference was detected in the biotransformation pattern of Org 6368 and pancuronium compared with controls. Inhibition of hepatic uptake of Org 6368 and pancuronium in extrahepatic cholestasis might explain the significant alterations in the pharmacokinetics of the two steroid neuromuscular blocking drugs. The pharmacokinetics of gallamine were normal during cholestasis. The results suggest that, under pathological conditions involving increased plasma concentrations of bile salts, neuromuscular blocking agents that are cleared from the plasma by the liver may have an impaired hepatic uptake and consequently a prolonged duration of action.

The influence of bile salts on hepatic transport of the organic anion dibromosulphthalein (DBSP) was investigated in rats. Bile salts influence the hepatic uptake, intracellular binding, and biliary excretion of DBSP. The overall effect depends on the administered dose of bile salts and DBSP. High doses of bile salts inhibited hepatic uptake of DBSP, whereas low doses of bile salts stimulated bile flow and simultaneously increased maximal biliary excretion of DBSP. The uncharged nonbile salt choleretic ouabain also stimulated biliary DBSP excretion. In contrast, the anionic nonbile salt choleretics, ethacrynic acid and theophylline, did not stimulate biliary excretion of DBSP. Because DBSP inhibited biliary excretion of ethacrynic acid and its metabolites, the lack of a stimulatory effect of ethacrynic acid choleresis might be explained by concomitant inhibition of biliary excretion of DBSP, masking the stimulatory effect of ethacrynic acid. Biliary transport maximum of DBSP was highly correlated with bile flow. The biliary clearance (Vmax/Km) was only moderately changed by bile salt administration, whereas the increase in the maximal biliary excretion rate was more pronounced, implying that the apparent Km for biliary excretion of DBSP was also increased by the bile salts. It is inferred that the stimulation of net biliary excretion of DBSP by bile salts may be due to a diminished transport from bile into the hepatocytes as the consequence of the decreased biliary concentration caused by the choleresis.

The renal and hepatic elimination and biotransformation, as well as the relation between disposition and duration of action of pancuronium and two of its analogues, dacuronium and ORG.6368, have been investigated in the cat. In pharmacokinetic studies, appreciable amounts of the latter two compounds were found in the urine, bile and liver 8 h after their intravenous administration. Various proportions of the injected dose of the respective drugs were metabolized. In another series of experiments it was shown that the early hepatic uptake (during the first 3 min after the injection) of ORG.6368 was significantly greater than that of dacuronium and pancuronium. The intensity and duration of action of the neuromuscular blocking effect of the three compounds were studied after intravenous and "close" intraarterial injection. On the basis of these pharmacokinetic and neuromuscular studies, it was concluded that the short duration of action of ORG.6368 is due primarily to its early hepatic uptake. The possibility cannot be excluded, however, that differences in the kinetics of the drug action of ORG.6368 and the other two compounds also contributed significantly to the differences seen in the duration of action of these compounds.

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